Académie royale de Médecine de Belgique

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Short Communications

Immunity and vaccine development against Streptococcus pyogenes: is emm-typing enough?     PDF
Pierre Smeesters     89-98

Abstract:
Serious disease caused by Streptococcus pyogenes (group A streptococcus, GAS), particularly rheumatic heart disease and invasive GAS infection, is responsible for more than half a million deaths worldwide per year. With no effective control strategies available for these diseases, a GAS vaccine is urgently needed. The development of a global GAS vaccine has been hindered by the large diversity of circulating strains (emm-types) of GAS in low-incomes settings. While approximately 80% coverage of the common emm-types in the USA and in Europe is theoretically possible with the 26 emm-type vaccine, the coverage in low-income settings, where serious GAS disease is most common, would be as low as 30%. Recent in vitro and in silico discoveries offer an exciting new approach to developing vaccines that protect against the broad range of strains in different regions of the world. These data suggest that antibodies against some emm-types may cross-protect against other emm-types. Cross protection between emm-types would represent a new paradigm in our understanding of immunity against GAS and an avenue for future GAS vaccine formulations.



Study of the activity of a potential new antibiotic (CSA-13) on biofilms formed by P. aeruginosa clinical isolates     PDF
Carole Nagant     99-103

Abstract:
The effect of an antimicrobial peptide mimic, the compound CSA-13, was studied on the different stages of the development of a biofilm formed by P. aeruginosa including on clinical strains isolated from the expectorations of patients with cystic fibrosis. Our results showed promising potential in using this cationic antibiotic steroid for the eradication of the biofilms formed by P. aeruginosa that are so deleterious in cystic fibrosis patients. The drug had also some synergy with tobramycin suggesting that a co-administration of CSA-13 and tobramycin should be considered for the treatment of chronic pulmonary infections provoked by P. aeruginosa.



The control of glucagon secretion by glucose and katp channel modulators     PDF
Patrick Gilon     129-145

Abstract:
Glucagon secreted by pancreatic α-cells is a hyperglycemic hormone which plays a major role in the correction of hypoglycemia. Its secretion is physiologically controlled by nutrients, hormones and neurotransmitters. The mechanisms by which glucose inhibits its release are poorly known. In particular, it is unclear whether the glucagonostatic effect of glucose results from a direct action on α-cells or an indirect mechanism involving the release of an inhibitory paracrine factor from insulin-secreting β-cells or somatostatin-secreting δ–cells. We briefly review the different hypotheses of the glucagonostatic effect of glucose, and present our own data. In particular, we show that in α-cells, as in β-cells, KATP channels transduce changes in cell metabolism into changes in membrane potential and Ca2+ influx through voltage-dependent Ca2+ channels. A direct closure of α-cell KATP channels stimulates glucagon release and, hence, would not be responsible of the glucagonostatic effect of glucose. By contrast, glucagon secretion is inhibited by somatostatin released from δ-cells and a direct closure of δ-cell KATP channels stimulates somatostatin release leading to inhibition of glucagon secretion. These direct and indirect effects of KATP channel closure from, respectively, α- and δ-cells should be kept in mind when using hypoglycemic sulfonylureas to treat diabetes and correct the chronic hyperglycemia.



MicroRNAs: new actors in acute myeloid leukemia.     PDF
Violaine Havelange     157-170

Abstract:
MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at post-transcriptional level mainly by messenger RNA (mRNA) degradation. Altered miRNA expression has been described in acute myeloid leukemia (AML) patients. The functions of most of these miRNAs in leukemogenesis are still unclear. By correlating miRNA and mRNA expression profiles in AML patients, we identified functional miRNA-mRNA interactions taking place within pathways controlling hematopoiesis, innate immunity, inflammation, apoptosis and chromatin remodeling. To explore the roles of miR-29b which is frequently down-regulated in AML patients, we showed that miR-29b restoration reduced cell growth and induced apoptosis in AML cell lines. MiR-29b dramatically reduced tumorigenecity in a xenograft model providing rationale for the use of miR-29b synthetic oligonucleotides as a novel strategy to improve treatment response in AML. MiR-29b was also involved in aberrant DNA methylation by targeting DNA methyltransferases suggesting another therapeutic role of synthetic miR-29b as hypomethylating agent in AML. Finally, miR-29b expression level was associated with clinical response to decitabine. Levels of miR-29b expression should be validated as a predictive factor for stratification of older AML patients to decitabine treatment (an hypomethylating agent).



Antisense strategies against DUX4 as a therapeutic approach for FSHD     PDF

Eugénie Ansseau     194-204

Abstract:
Facioscapulohumeral muscular dystrophy (FSHD) is a rare hereditary disease linked to a chromatin opening on the D4Z4 repeat array in 4q35 that allows expression of the DUX4 gene mapped by Prof. Alexandra Belayew’s group in the D4Z4 unit. We have characterized the DUX4 messenger RNAs (mRNA) in FSHD muscle: they derive from the last D4Z4 element and extend to the flanking pLAM region to a polyA signal which helps stabilize the mRNA. The DUX4 protein is a transcription factor and initiates a gene deregulation cascade causing defects, which are characteristics of the pathology. We propose to suppress DUX4 expression as a therapy for FSHD. In collaboration with Prof. Steve Wilton (Murdoch University - Western Australia), we have developed antisense oligomers (AO) specifically targeting the DUX4 mRNA which decreased DUX4 protein expression in myoblast cultures as well as its toxic effects.
For in vivo assays we used Prof. Scott Harper’s (Ohio State University, Columbus, USA) myopathy model caused by the injection of an AAV.DUX4 viral vector in a mouse hind limb muscle. In a first experiment our best AOs strongly decreased the amount of DUX4 mRNA in vivo.